Oliver Sartor, MD; Philip W. Kantoff, MD


June 10, 2014

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"Slam Dunk" for Metastatic Prostate Cancer

Oliver Sartor, MD: Hello. I am Dr. Oliver Sartor, Laborde Professor of Cancer Research in the Department of Medicine at Tulane University. I am also the Medical Director of the Tulane Cancer Center of Tulane Medical Center in New Orleans, Louisiana. Welcome to this edition of Medscape Oncology Insights on genitourinary cancer. We are going to be focusing on prostate cancer today and presentations from the 2014 annual meeting of the American Society of Clinical Oncology (ASCO®).

Joining me today is Dr. Phil Kantoff, Jerome and Nancy Kohlberg Chair of Medicine, Harvard Medical School, and Director of the Lank Center for Genitourinary Oncology at Dana-Farber in Boston, Massachusetts. Welcome, Phil.

Philip W. Kantoff, MD: Thanks, Oliver, good to be here.

Dr. Sartor: In the plenary session yesterday, we heard a tremendous talk. For people who might not have been able to attend, could you comment on the CHAARTED trial[1]?

Dr. Kantoff: The CHAARTED trial really impressed me, not only because it was a positive study, but because it was such a positive study. This dates back to the time when docetaxel was approved for metastatic castration-resistant prostate cancer. An obvious question at that time was whether we should move docetaxel up, in earlier disease in the metastatic hormone-sensitive group of patients. Chris Sweeney and ECOG did just that.

They conducted a trial with 790 patients who had metastatic hormone-sensitive prostate cancer and randomly assigned them to receive either standard androgen deprivation therapy or androgen deprivation therapy plus 6 cycles of docetaxel. Initially, the study was intended for high-risk patients, defined as patients with visceral metastases or 4 or more bone metastases. However, the accrual was a little slow, so they opened the trial later on to include some patients with less advanced but still metastatic hormone-sensitive prostate cancer.

In the study, about 64% of the patients had high-risk disease. There was an interim analysis in December 2013,[2] at which time a press release was issued announcing that the study was positive. We didn't hear the details of the study until yesterday.

I was surprised at just how positive it was. The median survival difference between the 2 groups was 14 months, which is the largest magnitude that I have seen in an advanced prostate cancer study, let alone in many other diseases.

Dr. Sartor: That is absolutely extraordinary. What about that high-risk subset that you mentioned?

Dr. Kantoff: About two thirds of the patients were in the high-risk category, and in that group of patients the median survival difference was 17 months. This was highly statistically significant, with a hazard ratio of 0.61, which is extraordinary. The toxicity was minimal. It's hard to compare across studies, but it seemed in general to be better tolerated in a hormone-sensitive, earlier population than it was in patients with metastatic castration-resistant prostate cancer. The incidence of hematologic and nonhematologic toxicities seemed to be lower.

Treating Patients in Un-CHAARTED Territory

Dr. Kantoff: The question is not whether this is going to change treatment patterns. This is a slam-dunk in terms of changing the way we look at hormone-sensitive prostate cancer and adding docetaxel to patients who are in that state, but where do you draw the line in regard to high-risk patients as defined by the study [4 or more bone metastases or visceral metastasis]? Mike Morris led a nice discussion in which he asked about that patient with 3 metastases, or 3 metastases but one of them a large metastasis. What about a particularly young individual? How are we going to individualize for the patients who are on the edge?

The next question that I have for you is, what are we going to do about the good-risk patients? In my mind, it's too early to treat good-risk metastatic hormone-sensitive prostate cancer patients with chemotherapy. The data are just not in on that subset of patients. There are too few events so far. It's a little early. Only one third of 790 patients in the study were in that category. For the patients in between, we are going to have to make individualized decisions about whether to give docetaxel chemotherapy. What is your sense at this point about where the line should be drawn and who you are going to treat? Do you think this is standard of care at this point?

Dr. Sartor: I do think it is standard of care. It's a game-changer. I was astounded by the 17-month difference in survival for that high-risk group. A difference of 4.1 months in castrate-resistant disease is great, and then all of a sudden we have a 17-month difference. This is big. Where we draw the line is a very interesting question. From my own perspective, I think about the volume of the disease, but I also think about the age of the patient and his comorbid conditions.

In a young man, I will probably have a tendency to think a little more aggressively. The one third of patients without the high-risk disease (by that definition) were actually doing pretty well on hormones alone. As it turns out, we are getting better at treating castrate-resistant prostate cancer, and I will probably use regular hormones in patients with oligometastatic disease of relatively low volume. How do you draw the line? In the end, it will be a judgment call. With respect to the high-risk patient, there is no question: I am going to be offering this to my patients.

Splice Variants: Potent Predictors of Response

Dr. Sartor: Let me move on to another study. Emmanuele Antonarakis[3] presented a very provocative small study looking at interim receptor variants. Would you tell us a little more about what an "interim receptor variant" is? He talked about an AR-V7 splice variant. Tell us about that conceptually, and what did Dr. Antonarakis show?

Dr. Kantoff: Splice variants of the estrogen and androgen receptors have been known for years now. More recently they are recognized in the androgen receptor, but previously they were noted in the estrogen receptor. These are generally truncated androgen receptors with a ligand binding domain. The area of the androgen receptor that binds to either testosterone or dihydrotestosterone is deleted. So you have a molecule and an androgen receptor variant that is capable of binding to DNA and potentially stimulating androgen binding sites in DNA and having ligand-independent activity.

Dr. Sartor: It sounds kind of scary.

Dr. Kantoff: Right. These have been observed in cell lines. They have also been demonstrated in xenographs to have stimulatory activity even in the hormone-depleted state. The question is, what is the clinical significance of these? To date, I don't think that anyone has demonstrated the clinical significance of splice variants in the case of estrogen receptors, and many of us were skeptical about whether these have any significance in prostate cancer.

There is a whole array of these splice variants -- there are probably 20 or more that we know about -- and maybe even more than that. Dr. Antonarakis and Changxue Lu, who discovered the AR-V7 splice variant, took a look at a series of patients who were treated with the 2 new antigen signaling agents (enzalutamide or abiraterone), and it was dramatic. If a splice variant was detectable in circulating tumor cells in these individuals, the likelihood of them responding to abiraterone or enzalutamide was almost zero. In one case it was zero. The numbers were small, but it was a very potent, negative predictor of response to these agents.

On the other hand, if the individual didn't have that AR-V7 variant, the likelihood of responding was actually higher than might be predicted, so this could be the first biomarker for distinguishing those individuals who respond to these secondary androgen-signaling agents.

It is incumbent on us to develop reliable assays to detect these variants, and this underscores the importance of trying to inhibit the N-terminus of the antigen receptor -- which seems, at least in the subset of prostate cancers, to be driving the cancer, rather than the ligand.

Coming Around to Circulating Tumor Cells

Dr. Kantoff: In terms of an assay for detecting the AR-V7 in circulating tumor cells, there are other ways to detect androgen-receptors and androgen-receptor variants and mutations, including circulating DNA. Do you want to speak to any news that you heard at ASCO about circulating DNA in patients?

Dr. Sartor: I do, but in the context of the blood biopsy, there has been a lot of excitement about being able to biopsy the tumor and make correlative studies to look at predictive biomarkers, indicating what is going to happen and when. It turns out that another way to study these particular biomarkers is looking at the circulating cells with the antibody-based methodology. You can use an N- and C-terminal antibody and find cells with N-terminal body positivity and C-terminal (which is the ligand domain) negativity.

It was very interesting that we are beginning to float into this circulating DNA mode now. In circulating DNA, there is annotation of mutations within the androgen receptor and the beginning of a delineation of the various landscapes of genomic changes. We are about to enter into a whole new era, when we have access to circulating genome that is at least in part derived from the tumor cells. It can be informative in our clinical decision-making. That is perhaps a bit of a stretch, but I don't think that it is too far a stretch to let our imagination go there.

Let me ask you one more question. There was a presentation by Eleni Efstathiou[4] about a protocol in which enzalutamide and abiraterone were given together. I was curious about your opinion on that.

Will Combination Therapy Extend Survival?

Dr. Kantoff: If you look at the landscape of metastatic castration-resistant prostate cancer and how it has changed, we have had several new drugs over the past 4 years. My overall take is that survival extension is about a year or so, maybe a little bit more than a year. If you add up the median survival advantages of each of the different agents that we have introduced (sipuleucel-T, abiraterone, enzalutamide, and radium-223) in addition to docetaxel, you would expect a longer improvement in survival. There is probably some degree of cross-resistance among these agents, and what has become very clear is that this cross-resistance is between the androgen-signaling agents enzalutamide and abiraterone. If you give one drug first, the ability to give the second drug is dampened; there is a lower response rate to the second drug, and it occurs whether you give abiraterone first and enzalutamide second, or enzalutamide first and abiraterone second. The question is whether combining them is going to improve the outcome, by potentially taking care of the cross-resistance mechanisms at the same time.

Eleni presented a very nice study of about 60 patients in whom she combined the 2 agents. It makes sense to combine them, but it needs to be proven. The response rates were a little bit better than with each agent individually. We don't have a sense of the duration or durability of the responses, but this question needs to be answered. Does it make sense to combine these agents, because it doesn't look very promising to sequence them? This will be looked at in the context of randomized studies.

Dr. Sartor: Could you comment on the Alliance trial[5] briefly for those who may not be familiar with it? In Alliance, the combination is being studied prospectively in a large randomized trial.

Dr. Kantoff: It is asking the question of whether giving the two together is better than giving them sequentially, and it is a very important and exciting study. The control arm is enzalutamide, so it is enzalutamide compared with enzalutamide plus abiraterone, and patients are able to cross over to abiraterone if and when they fail enzalutamide, or they can move on to other therapies.

The other study should be done as well, which is abiraterone plus or minus enzalutamide. There are sequencing questions that need to be asked and answered in the next few years. At least there are some studies that will help guide us.

Visceral Metastases Worsen Prognosis

Dr. Kantoff: Let me just ask you about one other study that I thought was interesting. This was Susan Halabi's[6] meta-analysis of 5 large randomized studies in metastatic castration-resistant prostate cancer that involved docetaxel, in which she asked the question of whether visceral involvement bodes a poor prognosis. The definition of visceral involvement was either lung or liver involvement. This was a definitive study. Do you want to comment?

Dr. Sartor: Absolutely. First of all, it was a beautiful study. Susan Halabi is a statistician at Duke who analyzes genitourinary trials. She combined data on almost 4000 individuals who were docetaxel-treated, and she nailed the question. The answer was that people with liver metastases did much worse than those with lung metastases, and those with lung metastases did worse than those with the nonvisceral metastases (typical bone and lymph node) that you see with prostate cancer. Of interest, if a patient had only node metastases, he did a little better.

Let me thank you -- it is always a pleasure to work with you. Thank you for joining us for Medscape Oncology Insights. This is Dr. Oliver Sartor, reporting from ASCO 2014.


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